The optimised design, protein engineering, mechanism of activation, and preclinical characterization of therapeutic strategies supporting (A) tumour localized cytokine activation (ex. ZW270, a conditionally activated IL-12) and (B) conditional anti-tumour T cell engagers with simultaneous checkpoint inhibition (ex. PROTECT) will be presented.

SNS-101, a novel, conditionally-active antibody, specifically targets the VISTA checkpoint in the acidic tumor microenvironment to enhance anti-tumour immunity and overcome resistance to checkpoint inhibitors. It overcomes previous safety and PK challenges, showing potential in combating immune checkpoint inhibitor resistance, as evidenced in preclinical studies (Thisted et al. Nat. Comm 2024). Currently in Phase I (NCT05864144), SNS-101 has shown selectivity for active VISTA, mitigating TMDD and reducing CRS risks.

We have designed antibody chain-exchange and chain-complementation approaches that can be used to generate conditionally active antibody prodrugs. The underlying principle is based on antibody-mediated targeting of two separate inactive entities, which results in the generation of functional bi- or multi-specific antibody derivatives upon accumulation on target cells. Examples that will be presented include prodrug approaches for tumour-activated T cell engagers and conditionally active antibody-cytokine fusions.

Six-transmembrane epithelial antigen of prostate-2 (STEAP2) is a complex membrane protein that is highly expressed on prostate cancer cells with limited distal normal tissue expression. High species homology and small extracellular domains makes STEAP2 a very challenging protein to target. I will share reflections on the multifaceted discovery campaigns that enabled the isolation of STEAP2-specific antibodies for the development of an armored STEAP2 chimeric antigen receptor T cell therapy.

Stimulation of 4-1BB with agonistic antibodies is a promising strategy for improving the therapeutic efficacy of immune checkpoint inhibitors (ICIs). However, cancer therapies based on activating antibodies to 4-1BB were hampered by adverse events such as liver toxicity in patients. To avoid this on-target liver toxicity, we developed a novel BsAb (Grabody T) uniquely designed to activate 4-1BB signaling only in the presence of TAA within the tumor microenvironment. On-going multiple Phase 1 trials including ABL503 (L14B; PD-L1x4-1BB) and Givastomig (ABL111; Claudin18.2x4-1BB) demonstrated superior efficacy and safety profile. In addition, we will present the combination strategy of Grabody T.

Despite the success of immunotherapies in cancer treatment, serious adverse events and potency loss remain significant challenges, often linked to antibody binding-affinity. For example, it was shown that a 15-fold change of affinity directly regulates CAR T cell activity, resulting in lower adverse effects. We developed a universal allosteric affinity-switch by incorporating engineered human-calmodulin linkers in antibody fragments, enabling remote-controlled adjustments to antibody affinity with a small ligand under physiological conditions, independent of the paratope. This approach enables both increased and decreased affinity in antibodies, offering a tunable strategy to enhance CAR T cell or T cell engager safety and efficacy in patients.

First-in-Human (FIH) Dose Selection is a key consideration in the drug development of new promising drug candidates. Such estimation involving cross-functional expertise and collaborations is essential for the design of efficient and successful Phase 1 clinical trials. FIH dose is based on the Regulatory requirements, and the concepts and strategy can differ depending on the biotherapeutic modality. This presentation will provide some insights of challenges and future considerations of the FIH dose estimation for 3 biologic molecules, i.e,. Monoclonal Ab, Antibody-Drug Conjugate (ADC), and an innovative Multispecific.

SCLC patients are faced with limited treatment options. T cell redirecting antibodies (TCB) show great promise but careful target selection remains essential. The tumour selectivity of the SCLC-associated glycolipid Fucosyl-GM1, its expression being virtually absent in normal tissues, enables TCB development.  SC134-TCB exhibits superb Fucosyl-GM1 specificity and T cell-mediated SCLC tumour control, representing an attractive development candidate for SCLC therapy.

• Fucosyl-GM1 is expressed by over 70% of SCLC tumours and virtually absent in normal tissues
• SC134-TCB targets Fucosyl-GM1 with great specificity and avidity
• SC134-TCB exerts strong tumour control ex vivo and in vivo through T cell redirection and activation in the TME
• These data support further development of SC134-TCB into an alternative treatment option for SCLC patients

Through the direct immunization of a nurse shark, we identified a suite of VNARs that were able to image fibroblast activation protein (FAP)-expressing cells in vivo by PET imaging and eliminate them when coupled to cytotoxins. Using next-generation sequencing, we developed a phylogenetic tree that allowed us to identify candidate VNARs with favorable targeting properties (rapid internalization, cross-reactivity with mouse FAP). We also determined the cryo-EM structures of several VNARs bound to FAP that demonstrated novel modes of target engagement.

The presentation outlines the development of a novel bispecific antibody that targets HER3, a receptor critical in cancer progression and resistance. This antibody simultaneously engages HER3 on various tumor cells and CD3 on T cells, initiating a potent but safe immune-mediated attack. We explore the engineering, mechanism of action, and notable anti-tumor efficacy demonstrated in preclinical studies, while also addressing safety concerns through observed reduced cytokine induction. Results indicate significant T-cell activation and tumor reduction, underscoring the therapeutic potential of this approach for diverse cancer types, with an enhanced safety profile.

We are developing Degrader-Antibody Conjugates (DACs) that target TROP-2 to treat Triple-Negative Breast Cancer (TNBC), leveraging Feline Mammary Carcinoma (FMC) as a comparative oncology model. We are exploring our single-domain antibody platform to develop a highly specific and potent DAC molecule. By advancing this innovative approach, we aim to provide new therapeutic options for both human and feline patients affected by TROP-2-positive cancers.